PROJECT SUMMARY ? PROJECT 2 The goal of our Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. Our focus is on the primary genetic risk factor for late-onset AD, the ?4 allele of apolipoprotein E (ApoE4), and how it is disproportionally affects AD risk in women. In particular, we will investigate interactions between several significant risk factors for AD: age, the ApoE4, and female sex. In Project 2, our specific emphasis is how ApoE4 interacts with female sex, perimenopause and adiposity to cooperatively drive development of AD pathology. Perimenopause initiates the age-related depletion of ovarian hormones in women. Perimenopause is also linked with increases in body weight and adiposity that often lead to obesity, an established risk factor for the development of AD. Significantly, adiposity and obesity are not only regulated by ovarian hormones, but also are known to impair bioenergetics and increase inflammation. Thus, perimenopause creates a dangerous convergence of AD risk factors in middle-aged women that we hypothesize is exacerbated by ApoE4. We hypothesize that the central unifying link between AD, ApoE, obesity and estrogen is inflammation. Pro- inflammatory pathways can function as critical driving forces in AD pathogenesis, are elevated by both ApoE4 genotype and obesity, and are inhibited by estrogen. To investigate these relationships, we propose three specific aims that are highly collaborative across all Cores and Projects. Specific Aim 1: ApoE genotype interactions in the regulation of inflammation and Alzheimer's pathways. We will compare the effects of ApoE alleles on expression of AD- and inflammation-related genes, AD neuropathology, metabolism, and cognition Specific Aim 2: Obesity and ApoE genotype interactions with female sex in the regulation of inflammation and Alzheimer's pathways. We will determine how ApoE status interacts with obesity in the regulation of AD- and inflammation-related pathways, AD neuropathology, metabolism and cognition. Specific Aim 3: Hormone interventions for protection against inflammation and Alzheimer's pathways associated with ApoE genotype, obesity and perimenopause. We will evaluate the efficacy of estrogen-based hormone therapies in attenuating the effects of ApoE4, in the presence and absence of obesity, during both perimenopause and late menopause.